Project Summary Primary progressive aphasia (PPA) is a clinical syndrome characterized by isolated, progressive loss of speech and language abilities. PPA occurs when pathological and molecular changes of frontotemporal lobar degeneration (FTLD) or Alzheimer's disease (AD) selectively damage language-specific networks of the brain. There is considerable variability in the distribution of brain atrophy in PPA, and patterns of language deficits vary accordingly. In particular, three clinical variants of PPA have been identified: i) logopenic variant (lvPPA) associated with loss of phonological abilities, left temporal-parietal atrophy and most often AD pathology; ii) nonfluent/agrammatic variant (nfvPPA) with motor speech and grammar deficits, left inferior frontal damage and often FTLD pathology; and iii) semantic variant (svPPA), with loss of conceptual knowledge, anterior temporal damage and also most often with FTLD-type pathology. This classification has greatly improved PPA diagnosis but clinical heterogeneity remains an issue, even within each variant, as individual patients differ in terms of their specific patterns of atrophy, language deficits and pathology. In the early stages of the disease, differential diagnosis between lvPPA and nfvPPA is particularly challenging as speech errors can occur in both conditions and atrophy might initially be subtle. To better distinguish between PPA variants, in this grant, we propose to examine neural oscillations in PPA using high temporal resolution brain imaging with magnetoencephalography (MEGI). We will examine regional neural oscillatory activity associated with speaking with a precision unmatched by any other imaging modality. MEGI data will be examined in conjunction with detailed cognitive and language testing, MRI and molecular PET imaging with the amyloid binding tracer PIB biomarker for AD that will be available in all our subjects. The specific aims are: 1. To identify differential patterns of frequency-specific resting-state oscillatory activity and functional connectivity in early stages of PPA variants 2. To examine cortical oscillatory network activity during speech feedback processing in PPA variants 3. To examine cortical oscillatory network activity during sequential speech production in PPA variants Overall, our findings will enable us to identify some of the earliest functional manifestations of brain network dysfunction in PPA, leading to the development of useful biomarkers to detect and longitudinally assess the progressive speech decline in PPA.